Azabicyclic carbamates and their use as alpha-7 nicotinic acetylcholine receptor agonists

ABSTRACT

The invention relates to novel benzothiophene-, benzofuran-, and indole ureas and to the use thereof for producing medicaments for the treatment and/or prophylaxis of diseases and for improving perception, concentration, learning, and/or memory.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/871,495, filed Aug. 30, 2010, now U.S. Pat. No. 8,153,799, which is acontinuation of U.S. patent application Ser. No. 10/522,611, filed Jan.27, 2005, now U.S. Pat. No. 7,795,453, which is the U.S. National Stageapplication under 35 U.S.C. §371 of International Patent ApplicationSerial No. PCT/EP2003/007588, filed Jul. 14, 2003, which claims thebenefit of German Patent Application No. 10234424.8, filed Jul. 29,2002, the disclosures of each of which are expressly incorporated byreference in their entireties.

The invention relates to novel benzothiophene-, benzofuran- andindoleureas, processes for their preparation, and their use forproducing medicaments for the treatment and/or prophylaxis of diseasesand for improving perception, concentration, learning and/or memory.

Nicotinic acetylcholine receptors (nAChR) form a large family of ionchannels which are activated by the messenger acetylcholine which isproduced in the body (Galzi et al., Neuropharmacol. 1995, 34, 563-582).A functional nAChR consists of five subunits which may be different(certain combinations of α1-9 and (β1-4,γ,δ,ε subunits) or identical(α7-9). This leads˜to the formation of a diversity of subtypes whichdiffer in the distribution in the muscles, the nervous system and otherorgans (McGehee et al., Annu. Rev. Physiol, 1995, 57, 521-546).Activation of nAChR leads to influx of cations into the cell and tostimulation of nerve cells or muscle cells. Selective activation ofindividual nAChR subtypes restricts this stimulation to the cell typeswhich have a corresponding subtype and is thus able to avoid unwantedside effects such as, for example, stimulation of nAChR in the muscles.Clinical experiments with nicotine and experiments in various animalmodels indicate that central nicotinic acetylcholine receptors areinvolved in learning and memory processes (e.g. Rezvani et al., Biol.Psychiatry 2001, 49, 258-267). Nicotinic acetylcholine receptors of thealpha7 subtype (a7 nAChR) have a particularly high concentration inregions of the brain which are important for learning and memory, suchas the hippocampus and the cerebral cortex (Séguéla et al., J. Neurosci.1993, 13, 596-604). The α7 nAChR has a particularly high permeabilityfor calcium ions, increases glutamatergic neurotransmission, influencesthe growth of axons and, in this way, modulates neuronal plasticity(Broide et al., Mol. Neurobiol. 1999, 20, 1-16).

Certain N-(1-azabicyclo[2.2.2]oct-3-yl)heteroaryl carboxamides for thetreatment of, inter alia, psychoses are described in DE-A 37 24 059.

N-(Azabicycloalkyl)heteroaryl carboxamides, in particularN-(1-azabicyclo[2.2.2]oct-4-yl)benzothiophene-3-carboxamides, aredisclosed in WO 93/15073 and in EP-A 485 962 as intermediates for thesynthesis of pharmaceutically active compounds.

U.S. Pat. No. 4,605,652 and EP-A 372 335 disclose, for example,N-(1-azabicyclo[2.2.2]oct-3-yl)thiophene-2-carboxamide and itsmemory-improving effect.

JP-A 14 030 084 describes 1-azabicycloalkanes for the treatment of,inter alia, dementia, attention deficit hyperactivity disorder andimpairments of learning and memory.

The present invention relates to compounds of the formula

in which

-   R¹ is 1-azabicyclo[2.2.2]oct-3-yl,-   R² is hydrogen or C₁-C₆-alkyl,-   R³ is hydrogen, halogen, amino, hydroxy or C₁-C₆-alkyl,-   R⁴ is hydrogen, C₁-C₆-alkyl which is optionally substituted by a    radical selected from the group of hydroxy, halogen, cyano,    C₁-C₆-alkoxy, trifluoromethyl, trifluoromethoxy,-   R⁵ is hydrogen or C₁-C₆-alkyl, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    are a 5- to 6-membered heterocycle which is optionally substituted    by up to 2 substituents independently of one another selected from    the group of C₁-C₆-alkyl, C₁-C₄-acyl, oxo, thioxo,-   R⁶ is (i) hydrogen, (ii) C₁-C₆-alkyl, (iii) C₃-C₈-cycloalkyl, (iv)    C₆-C₁₀-aryl, (v) 5- to 10-membered heteroaryl, (vi)    C₆-C₁₀-arylcarbonyl, where (ii) is optionally substituted by phenyl,    C₁-C₆-alkoxycarbonyl or C₁-C₆-alkoxy, and (iv), (v) and (vi) are    optionally substituted by up to 3 radicals selected independently of    one another from the group of C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, 3- to    8-membered heterocyclyl, C₆-C₁₀-aryl, 5- to 10-membered heteroaryl,    hydroxy, halogen, cyano, C₁-C₆-alkoxy, C₁-C₆-acyl, trifluoromethyl,    trifluoromethoxy, nitro, amino, C₁-C₆-alkylamino, C₁-C₆-acylamino,    or-   R⁵ and R⁶ together with the nitrogen atom to which they are bonded    are a 3- to 10-membered heterocycle which is optionally substituted    by C₁-C₆-alkyl or C₁-C₆-hydroxyalkyl,-   A is oxygen, nitrogen or sulfur,-   X is oxygen or sulfur,-   the ring B is benzo or pyrido, each of which are optionally    substituted by radicals from the series halogen, cyano,    trifluoromethyl, trifluoromethoxy, nitro, amino, C₁-C₆-alkyl and    C₁-C₆-alkoxy,    and the solvates, salts or solvates of the salts of these compounds.

Solvates is the term used for the purposes of the invention for thoseforms of the compounds which form a complex with solvent molecules bycoordination in the solid or liquid state. Hydrates are a special formof solvates in which the coordination takes place with water.

Salts which are preferred for the purposes of the invention arephysiologically acceptable salts of the compounds of the invention.

Physiologically acceptable salts of the compounds (I) may be acidaddition salts of the compounds with mineral acids, carboxylic acids orsulfonic acids. Particularly preferred examples are salts withhydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid,benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionicacid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acidor benzoic acid.

However, physiologically acceptable salts of the compounds (I) are alsosalts with conventional bases, such as, for example, alkali metal salts(e.g. sodium or potassium salts), alkaline earth metal salts (e.g.calcium or magnesium salts) or ammonium salts derived from ammonia ororganic amines such as, for example, diethylamine, triethylamine,ethyldiisopropylamine, procaine, dibenzylamine, N-methylmorpholine,dihydroabiethylamine, 1-ephenamine or methylpiperidine.

The compounds of the invention may exist in stereoisomeric forms(enantiomers, diastereomers). The invention therefore relates both tothe enantiomers or diastereomers and to respective mixtures thereof.These enantiomer and diastereomer mixtures can be separated in a knownmanner into the stereoisomerically pure constituents.

For the purposes of the present invention, the substituents generallyhave the following meaning:

C₁-C₆-alkoxy is a straight-chain or branched alkoxy radical having 1 to6, preferably 1 to 4, particularly preferably 1 to 3, carbon atoms.Nonlimiting examples include methoxy, ethoxy, n-propoxy, isopropoxy,tert-butoxy, n-pentoxy and n-hexoxy.

C₁-C₆-alkoxycarbonyl is a straight-chain or branched alkoxy carbonylradical having 1 to 6, preferably 1 to 4 and particularly preferably 1to 3, carbon atoms. Nonlimiting examples include methoxycarbonyl,ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl andtert-butoxycarbonyl.

C₁-C₆-alkyl is a straight-chain or branched alkyl radical having 1 to 6,preferably 1 to 4, particularly preferably 1 to 3, carbon atoms.Nonlimiting examples include methyl, ethyl, n-propyl, isopropyl,tert-butyl, n-pentyl and n-hexyl.

C₁-C₆-acyl is a straight-chain or branched acyl radical having 1 to 6,preferably 1 to 4, carbon atoms. Nonlimiting examples include acetyl,ethylcarbonyl, propylcarbonyl, isopropylcarbonyl, butylcarbonyl,isobutylcarbonyl, pentylcarbonyl and hexylcarbonyl. Acetyl andethylcarbonyl are preferred.

C₃-C₈-cycloalkyl is cyclopropyl, cyclopentyl, cyclobutyl, cyclohexyl,cycloheptyl or cyclooctyl. Those which may be mentioned as preferredare: cyclopropyl, cyclopentyl and cyclohexyl.

C₁-C₆-acylamino is an amino group having a straight-chain or branchedalkanoyl substituent which has 1 to 6 carbon atoms and is linked via thecarbonyl group. An acylamino radical having 1 to 2 carbon atoms ispreferred. Nonlimiting examples include formamido, acetamido,propionamido, n-butyramido and pivaloylamido.

C₁-C₆-alkylamino is a straight-chain or branched mono- or dialkylaminoradical having 1 to 6 carbon atoms. Preference is given to astraight-chain or branched alkylamino radical having 1 to 4,particularly preferably having 1 to 3, carbon atoms. Nonlimitingexamples include methylamino, ethylamino, n-propylamino, isopropylamino,tert-butylamino, n-pentylamino and n-hexylamino, dimethylamino,diethylamino, di-n-propylamino, diisopropylamino, di-t-butylamino,di-n-pentylamino, di-n-hexylamino, ethylmethylamino,isopropylmethylamino, n-butylethylamino, n-hexyl-i-pentylamino.

C₁-C₆-hydroxyalkyl is a straight-chain or branched hydroxyalkyl radicalhaving 1 to 6 carbon atoms which is linked via the alkyl group.Preference is given to a straight-chain or branched hydroxyalkyl radicalhaving 1 to 4, particularly preferably having 1 to 3, carbon atoms.Nonlimiting examples include hydroxymethyl, hydroxyethyl,3-hydroxypropyl, hydroxyisopropyl, hydroxy-tert-butyl, 5-hydroxypentyland 6-hydroxyhexyl.

3- to 8-membered heterocyclyl is a cycloalkyl group having 3 to 8,preferably 5 to 7, carbon atoms, with up to 2 ring carbon atoms in thecycloalkyl group having been replaced by a nitrogen atom and/or afurther heteroatom selected from the group of nitrogen, oxygen orsulfur, and the radical is attached via one of the ring nitrogen atoms.Examples which may be mentioned as preferred are: pyrazolidin-1-yl,piperazin-1-yl, perhydro-1,4-diazepin-1-yl, morpholin-1-yl,piperidin-1-yl.

3- to 10-membered heterocyclyl is a mono- or bicyclic cycloalkyl grouphaving 3 to 10, preferably 5 to 8, carbon atoms, with up to 2 ringcarbon atoms in the cycloalkyl group having been replaced by a nitrogenatom and/or a further heteroatom selected from the group of nitrogen,oxygen or sulfur, and the radical is attached via one of the ringnitrogen atoms. Examples which may be mentioned as preferred are:pyrazolidin-1-yl, piperazin-1-yl, perhydro-1,4-diazepin-1-yl,morpholin-1-yl, thiomorpholin-1-yl, piperidin-1-yl,azabicyclo[3.2.0]heptyl, azabicyclo[3.2.1]heptyl,azabicyclo[3.2.2]heptyl, azabicyclo[3.2.1]octyl, azabicyclo[3.2.2]octyl.

C₆-C₁₀-aryl is a mono- or bicyclic aromatic, carbocyclic radical usuallyhaving 6 to 10 carbon ring atoms. Nonlimiting examples include phenyland naphthyl.

C₆-C₁₀-arylcarbonyl is a mono- or bicyclic arylcarbonyl radical usuallyhaving 6 to 10 carbon ring atoms. Nonlimiting examples includephenylcarbonyl and naphthylcarbonyl.

5- to 10-membered heteroaryl is an aromatic mono- or bicyclic radicalusually having 5 to 10, preferably 5 to 6, ring atoms and up to 5,preferably up to 4, hetero ring atoms from the series S, O and N.Nonlimiting examples include thienyl, furyl, pyrrolyl, thiazolyl,oxazolyl, imidazolyl, pyridyl, pyrimidyl, pyridazinyl, indolyl,indazolyl, benzofuranyl, benzothiophenyl, quinolinyl, isoquinolinyl.

Halogen is fluorine, chlorine, bromine and iodine. Fluorine, chlorineand bromine are preferred, and fluorine and chlorine are particularlypreferred.

When radicals in the compounds of the invention are optionallysubstituted, unless indicated otherwise the radicals may have one ormore identical or different substituents.

Preference is given to compounds of the formula (I), in which

-   R¹ is 1-azabicyclo[2.2.2]oct-3-yl,-   R² is hydrogen or C₁-C₄-alkyl,-   R³ is hydrogen, halogen, amino, hydroxy or C₁-C₄-alkyl,-   R⁴ is hydrogen or C₁-C₄-alkyl which is optionally substituted by a    radical selected from the group of hydroxy, C₁-C₃-alkoxy,    trifluoromethyl, trifluoromethoxy,-   R⁵ is hydrogen or C₁-C₄-alkyl, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    are a 5- to 6-membered heterocycle which is optionally substituted    by up to 2 substituents independently of one another selected from    the group of C₁-C₆-alkyl, C₁-C₄-acyl, oxo, thioxo,-   R⁶ is (i) hydrogen, (ii) C₁-C₄-alkyl, (iii) C₅-C₆-cycloalkyl, (iv)    phenyl, (v) 5- to 6-membered heteroaryl, where (ii) is optionally    substituted by phenyl, and (iv) and (v) are optionally substituted    by up to 3 radicals selected independently of one another from the    group of C₁-C₄-alkyl, C₁-C₄-hydroxyalkyl, hydroxy, chlorine,    fluorine, cyano, C₁-C₃-alkoxy, C₁-C₆-acyl, trifluoromethyl,    trifluoromethoxy, amino, C₁-C₃-alkylamino, C₁-C₃-acylamino, or-   R⁵ and R⁶ together with the nitrogen atom to which they are bonded    are a 5- to 6-membered heterocycle which is optionally substituted    by C₁-C₃-alkyl or C₁-C₃-hydroxyalkyl,-   A is oxygen, nitrogen or sulfur,-   X is oxygen and-   the ring B is benzo or pyrido, each of which are optionally    substituted by radicals from the series chlorine, fluorine, cyano,    trifluoromethyl, trifluoromethoxy, amino, C₁-C₄-alkyl and    C₁-C₄-alkoxy,    and the solvates, salts or solvates of the salts of these compounds.

Preference is likewise given to compounds of the formula (I) in which

-   R¹ is 1-aza-bicyclo[2.2.2]oct-3-yl,-   R² is hydrogen or C₁-C₄-alkyl,-   R³ is hydrogen, halogen, amino, hydroxy or C₁-C₄-alkyl,-   R⁴ is hydrogen, C₁-C₄-alkyl which is optionally substituted by a    radical selected from the group of hydroxy, halogen, cyano,    C₁-C₃-alkoxy, trifluoromethyl, trifluoromethoxy,-   R⁵ is hydrogen or C₁-C₄-alkyl, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    are a 5- to 6-membered heterocycle which is optionally substituted    by up to 2 substituents independently of one another selected from    the group of C₁-C₆-alkyl, C₁-C₄-acyl, oxo, thioxo,-   R⁶ is (i) hydrogen, (ii) C₅-C₆-cycloalkyl, (iv) phenyl, (v) 5- to    6-membered heteroaryl, (vi) C₆-C₁₀-arylcarbonyl, where (ii) is    optionally substituted by phenyl, C₁-C₄-alkoxycarbonyl or    C₁-C₃-alkoxy, and (iv), (v) and (vi) are optionally substituted by    up to 3 radicals selected independently of one another from the    group of C₁-C₄-alkyl, C₁-C₄-hydroxyalkyl, 3- to 8-membered    heterocyclyl, C₆-C₁₀-aryl, 5- to 10-membered heteroaryl, hydroxy,    fluorine, chlorine, cyano, C₁-C₃-alkoxy, C₁-C₃-acyl,    trifluoromethyl, trifluoromethoxy, nitro, amino, C₁-C₃-alkylamino,    C₁-C₃-acylamino, or-   R⁵ and R⁶ together with the nitrogen atom to which they are bonded    are a 3- to 10-membered heterocycle which is optionally substituted    by C₁-C₃-alkyl or C₁-C₃-hydroxyalkyl,-   A is oxygen or sulfur,-   X is oxygen,-   the ring B is benzo or pyrido, each of which are optionally    substituted by radicals from the series chlorine, fluorine, cyano,    trifluoromethyl, trifluoromethoxy, amino, C₁-C₄-alkyl and    C₁-C₄-alkoxy,    and the solvates, salts or solvates of the salts of these compounds.

Preference is likewise given to compounds of the formula (I) in which

-   R¹ is 1-azabicyclo[2.2.2]oct-3-yl,-   R² is hydrogen,-   R³ is hydrogen, chlorine, fluorine, amino or C₁-C₃-alkyl,-   R⁴ is hydrogen, methyl or ethyl, where methyl and ethyl are    optionally substituted by a radical selected from the group of    hydroxy, methoxy, ethoxy, trifluoromethyl, trifluoromethoxy, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    are a 5- to 6-membered heterocycle which is optionally substituted    by up to 2 substituents independently of one another selected from    the group of C₁-C₃-alkyl, C₁-C₄-acyl, oxo, thioxo,-   R⁵ is hydrogen or C₁-C₃-alkyl,-   R⁶ is (i) hydrogen, (ii) C₁-C₄-alkyl, (iii) cyclopentyl,    cyclohexyl, (iv) phenyl, (v) benzyl, (vi) phenethyl, where (iv)    to (vi) are optionally substituted by up to 3 radicals selected    independently of one another from the group of hydroxy, chlorine,    fluorine, cyano, methoxy, ethoxy, C₁-C₄-acyl, trifluoromethyl,    trifluoromethoxy, amino, C₁-C₃-allylamino,-   A is oxygen or sulfur,-   X is oxygen and-   the ring B is benzo which is optionally substituted by radicals from    the series chlorine, fluorine, cyano, trifluoromethyl,    trifluoromethoxy, C₁-C₄-alkyl, methoxy and ethoxy,    and the solvates, salts or solvates of the salts of these compounds.

Preference is likewise given to compounds of the formula (I) in which

-   R¹ is 1-azabicyclo[2.2.2]oct-3-yl,-   R² to R⁴ are hydrogen,-   R⁵ is hydrogen or C₁-C₄-alkyl, or-   R⁴ and R⁵ together with the nitrogen atom to which they are bonded    are a 5- to 6-membered heterocycle which is optionally substituted    by up to 2 substituents independently of one another selected from    the group of C₁-C₄-alkyl, C₁-C₄-acyl, oxo, thioxo,-   R⁶ is (i) hydrogen, (ii) C₁-C₄-alkyl, (iii) C₅-C₆-cycloalkyl, (iv)    phenyl, (v) pyridyl, (vi) C₆-C₁₀-arylcarbonyl, where (ii) is    optionally substituted by phenyl, C₁-C₄-alkoxycarbonyl or    C₁-C₃-alkoxy, and (iv), (v) and (vi) are optionally substituted by    up to 3 radicals selected independently of one another from the    group of C₁-C₄-alkyl, C₁-C₄-hydroxyallyl, 3- to 8-membered    heterocyclyl, C₆-C₁₀-aryl, 5- to 10-membered heteroaryl, hydroxy,    fluorine, chlorine, cyano, C₁-C₃-alkoxy, C₁-C₃-acyl,    trifluoromethyl, trifluoromethoxy, nitro, amino, C₁-C₃-alkylamino,    C₁-C₃-acylamino, or-   R⁵ and R⁶ together with the nitrogen atom to which they are bonded    are a 3- to 10-membered heterocycle which is optionally substituted    by C₁-C₃-alkyl or C₁-C₃-hydroxyalkyl,-   A is oxygen or sulfur,-   X is oxygen,-   the ring B is benzo,    and the solvates, salts or solvates of the salts of these compounds.

Preference is likewise given to compounds of the formula

in which R¹ to R⁶, A and X have the meanings indicated above, and thesolvates, salts or solvates of the salts of these compounds.

Preference is likewise given to compounds of the formula

in which R¹ to R⁶, A and X have the meanings indicated above, and thesolvates, salts or solvates of the salts of these compounds.

Preference is likewise given to compounds of the formula

in which R¹ to R⁶ have the meanings indicated in claims 1 to 6, and thesolvates, salts or solvates of the salts of these compounds.

Preference is likewise given to compounds of the formula

in which R¹ to R⁶ have the meanings indicated in claims 1 to 6, and thesolvates, salts or solvates of the salts of these compounds.

Preference is likewise given to compounds of the formulae (Ia) and (Ib)in which R¹ to R⁶ have the meanings indicated above, and A and X areoxygen, and the solvates, salts or solvates of the salts of thesecompounds.

Preference is likewise given to compounds of the formulae (I) in whichR¹ is (3R)-1-azabicyclo[2.2.2]oct-2-yl, and R² to R⁶, A, X and the ringB have the meanings indicated above, and the solvates, salts or solvatesof the salts of these compounds.

Preference is likewise given to compounds of the formula (I) in which R²is hydrogen, and R¹, R³ to R⁶, A, X and the ring B have the meaningsindicated above, and the solvates, salts or solvates of the salts ofthese compounds.

Preference is likewise given to compounds of the formula (I) in which R³is hydrogen: fluorine or methyl, and R¹, R², R⁴ to R⁶, A, X and the ringB have the meanings indicated above, and the solvates, salts or solvatesof the salts of these compounds.

Preference is likewise given to compounds of the formula (I) in which R³is hydrogen, chlorine or methyl, and R¹, R², R⁴ to R⁶, A, X and the ringB have the meanings indicated above, and the solvates, salts or solvatesof the salts of these compounds.

Preference is likewise given to compounds of the formula (I) in which R³is hydrogen, and R¹, R², R⁴ to R⁶, A, X and the ring B have the meaningsindicated above, and the solvates, salts or solvates of the salts ofthese compounds.

Preference is likewise given to compounds of the formula (I) in which R⁴is hydrogen or C₁-C₆-alkyl which is optionally substituted by a radicalselected from the group of hydroxy, C₁-C₆-alkoxy, trifluoromethyl,trifluoromethoxy, and R¹ to R³, R⁵, R⁶, A, X and the ring B have themeanings indicated above, and the solvates, salts or solvates of thesalts of these compounds.

Particular preference is given to compounds of the formula (I) in whichR⁴ is hydrogen, methyl or ethyl, where methyl and ethyl is optionallysubstituted by a radical selected from the group of hydroxy, methoxy,ethoxy, trifluoromethyl, trifluoromethoxy, and R¹ to R³, R⁵, R⁶, A, Xand the ring B have the meanings indicated above, and the solvates,salts or solvates of the salts of these compounds.

Preference is likewise given to compounds of the formula (I) in which R⁵is hydrogen, and R¹ to R⁴, R⁶, A, X and the ring B have the meaningsindicated above, and the solvates, salts or solvates of the salts ofthese compounds.

Preference is likewise given to compounds of the formula (I) in which Xis an oxygen atom, and R¹ to R⁶, A and the ring B have the meaningsindicated above, and the solvates, salts or solvates of the salts ofthese compounds.

Preference is likewise given to compounds of the formula (I) in which Ais an oxygen atom, and R¹ to R⁶, X and the ring B have the meaningsindicated above, and the solvates, salts or solvates of the salts ofthese compounds.

Preference is likewise given to compounds of the formula (I) in whichthe ring B is benzo which is optionally substituted by 1 to 3 radicalsfrom the series halogen, cyano, trifluoromethyl, trifluoromethoxy andC₁-C₄-alkyl, and R¹ to R⁶, A and X have the meanings indicated above,and the solvates, salts or solvates of the salts of these compounds.

Very particular preference is given to combinations of two or more ofthe preferred ranges mentioned above.

The invention further relates to process for preparing the compounds ofthe invention, in which compounds of the formula

in which

-   R¹ to R⁴, A and B have the abovementioned meanings, are reacted    with compounds of the formula

in which

-   X and R⁶ have the abovementioned meanings,    and the resulting compounds (I) are reacted where appropriate with    the appropriate (a) solvents and/or (b) bases or acids to give the    solvates, salts or solvates of the salts thereof.

The reaction can take place in inert solvents, where appropriate in thepresence of a base, preferably in a temperature range from 20° C. to 60°C. under atmospheric pressure.

Examples of inert solvents are halohydrocarbons such as methylenechloride, trichloromethane, tetrachloromethane, trichloroethane,tetrachloroethane, 1,2-dichloroethane or trichloroethylene, ethers suchas diethyl ether, methyl tert-butyl ether, dioxane, tetrahydrofuran,glycol dimethyl ether or diethylene glycol dimethyl ether, hydrocarbonssuch as benzene, xylene, toluene, hexane, cyclohexane or petroleumfractions, nitroalkanes such as nitromethane, carboxylic esters such asethyl acetate, ketones such as acetone or 2-butanone, optionallyN-alkylated carboxamides, such as dimethylformamide ordimethylacetamide, alkyl sulfoxides such as dimethyl sulfoxide,carbonitriles such as acetonitrile or heteroaromatic compounds such aspyridine. Dimethylformamide or tetrahydrofuran are preferred.

Examples of bases are alkali metal hydroxides such as sodium orpotassium hydroxide, alkali metal carbonates and bicarbonates such ascesium carbonate, sodium bicarbonate, sodium or potassium carbonate, oramides such as lithium diisopropylamide, alkylamines such astriethylamine, diisopropylethylamine or DBU, preferablydiisopropylethylamine or triethylamine.

Synthesis of compounds (I) can take place according to Satchell, Chem.Soc. Rev. 1975, 4, 231-250 or Glebova, Russ. Chem. Rev. 1985, 59,249-261.

Compounds (II) can be synthesized by known processes from theappropriate bromo- or nitro-substituted precursors. Thus, they can besynthesized for example from the bromo-substituted aromatic compounds bypalladium-catalyzed reactions for example according to J. P. Wolfe etal., Tetrahedron Lett. 1997, 38, 6367-6370.

The nitro group of the nitro-substituted precursors can be reduced bycatalytic hydrogenation, for example according to Rylander,Hydrogenation Methods, Academic Press: New York, 1967 or Babler,Sarussi, Synth. Commun. 1981, 11, 925.

The invention further relates to the process for preparing the compoundsof the formula

in which

-   R¹ to R³, A and the ring B have the abovementioned meanings, and-   Y is bromine, nitro or —NH(PG), where PG is a protective group for    the amino function, for example tert-butyloxycarbonyl or    benzyloxycarbonyl,    characterized in that compounds of the formula    R¹R²NH  (V),    in which R¹ and R² have the abovementioned meanings, are reacted    with a compound of the formula

in which R³, A and the ring B have the abovementioned meanings, and

-   D is hydroxy, halogen, mesyloxy or isobutyloxycarbonyloxy,    preferably hydroxy and chlorine.

The reaction can take place in inert solvents, where appropriate in thepresence of a base and/or of a condensing agent, preferably in atemperature range from 0° C. to 50° C. under atmospheric pressure.

Preferred inert solvents include dioxane, dimethylformamide andmethylene chloride.

Examples of bases are alkali metal hydroxides such as sodium orpotassium hydroxide, alkali metal carbonates and bicarbonates such ascesium carbonate, sodium bicarbonate, sodium or potassium carbonate, oramides such as lithium diisopropylamide, alkylamines such astriethylamine, diisopropylethylamine or DBU, preferablydiisopropylethylamine or triethylamine and DBU.

Condensing agents for the purposes of the invention are, for example,carbodiimides such as, for example, N,N′-diethyl-, N,N′-dipropyl-,N,N′-dicyclo-hexylcarbodiimide,N-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),N-cyclohexylcarbodiimide-N′-propyloxymethylpolystyrene(PS-carbodiimide); carbonyl compounds such as carbonyldiimidazole;1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfateor 2-tert-butyl-5-methylisoxazolium perchlorate; acylamino compoundssuch as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline; in additionpropanephosphonic anhydride, isobutyl chloroformate,bis(2-oxo-3-oxazolidinyl)phosphoryl chloride,benzotriazolyloxy-tri(dimethylamino)phosphonium hexafluorophosphate,0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), 2-(2-oxo-1-(2H)-pyridyl)-1,1,3,3-tetramethyluroniumtetrafluoroborate (TPTU),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), and mixtures thereof.

It may be advantageous where appropriate to use the condensing agent inthe presence of an auxiliary nucleophile such as, for example,1-hydroxybenzotriazole (HOBt).

Particular preference is given to the combination ofN-(3-dimethylaminoisopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),1-hydroxybenzotriazole (HOBt) and triethylamine in dimethylformamide orof O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) and diisopropylethylamine indimethylformamide.

The compounds (V) and (IV) are known or can be synthesized in analogy toknown processes from the appropriate precursors (cf., for example,“Comprehensive Heterocyclic Chemistry”, Katritzki et al., editors;Elsevier, 1996). Thus, for example, substitutedbenzothiophene-2-carboxylic acids can be obtained from appropriatelysubstituted 2-halobenzaldehydes by reaction with methyl mercaptoacetate(see, for example, A. J. Bridges et al., Tetrahedron Lett. 1992, 33,7499) and subsequent hydrolysis of the ester:

The corresponding pyrido derivatives can be synthesized starting from2-halobenzonitriles by reaction with methyl mercaptoacetate to give the3-amino-benzothiophene-2-carboxylic esters:

Substituted benzofuran-2-carboxylic acids can be obtained for example asdescribed by D. Bogdal et al., Tetrahedron 2000, 56, 8769.

Derivatives of indole-2-carboxylic acids can be prepared by knownprocesses: D. A. Allen, Synth. Commun. 1999, 29, 447; C. W. Holzapfel,C. Dwyer, Heterocycles 1998, 48, 1513; M. Akazome et al., J. Org. Chem.1994, 59, 3375.

The radical R³ can be introduced for example by reacting suitablysubstituted ketones with methyl mercaptoacetate in accordance withsynthesis scheme 1 (J. A. Valderama, C. Valderama, Synth. Commun. 1997,27, 2143). Further methods for introducing halogen, amino or hydroxy atthis position are known from the literature: W. N. Lok, A. D. Ward,Aust. J. Chem. 1978, 31, 605; W. Reid et al., Liebigs Ann. Chem. 1980,1424; C. M. Bonnin et al., Aust. J. Chem. 1979, 32, 883; P. Martin, T.Winkler, Helv. Chim. Acta 1994, 77, 100; A. J. Bridges, H. Zhou, J.Heterocycl. Chem. 1997, 34, 1163; J. R. Beck, J. Org. Chem. 1973, 38,4086; T. K. Shkintova et al., Tetrahedron Lett. 2000, 41, 4973

Synthesis of the corresponding pyrido derivatives is possible startingfrom 2-halobenzonitriles by reacting with methyl mercaptoacetate to givethe 3-aminobenzo-thiophene-2-carboxylic esters:

The nitrogen atom shown in the ring may replace a CH group at one ofpositions 1 to 4 in the aromatic system.

The amino function can be removed by diazotization. Finally, the estercan be hydrolyzed to give the target compound.

The process described above can be illustrated by way of example via thefollowing formula diagram:

Modification of the last step as shown in the following scheme makes itpossible to synthesize trisubstituted ureas where R⁵ and R⁶ may formwith the nitrogen atom to which they are bonded a heterocycle.

A further possibility is to obtain asymmetrically substituted ureas alsoby using suitable phosgene derivatives such as, for example,p-nitrophenyl chloroformate (cf.: N. Choy et al., Org. Prep. Proced.Int. 1996, 28, 173), starting from variously substituted amines.

The compounds of the invention are suitable for use as medicaments forthe treatment and/or prophylaxis of diseases in humans and animals.

They act as α7 nAChR agonists and show a valuable range ofpharmacological effects which could not have been predicted.

The compounds of the invention can, because of their pharmacologicalproperties, be employed alone or in combination with other activeingredients for the treatment and/or prevention of cognitiveimpairments, especially of Alzheimer's disease. Because of theirselective effect as α7 nAChR agonists, they are particularly suitablefor improving perception, concentration, learning or memory, especiallyafter cognitive impairments like those occurring for example in mildcognitive impairment, age-associated learning and memory impairments,age-associated memory loss, vascular dementia, craniocerebral trauma,stroke, dementia occurring after strokes (post-stroke dementia),post-traumatic craniocerebral trauma, general concentration impairments,concentration impairments in children with learning and memory problems,attention deficit hyperactivity disorder, Alzheimer's disease, Lewy bodydementia, dementia with degeneration of the frontal lobes, includingPick's syndrome, Parkinson's disease, progressive nuclear palsy,dementia with corticobasal degeneration, amyotrophic lateral sclerosis(ALS), Huntington's disease, multiple sclerosis, thalamic degeneration,Creutzfeld-Jacob dementia, HIV dementia, schizophrenia, schizophreniawith dementia or Korsakoffs psychosis.

The compounds of the invention can be employed alone or in combinationwith other active ingredients for the prophylaxis and treatment of acuteand/or chronic pain (for a classification, see “Classification ofChronic Pain, Descriptions of Chronic Pain Syndromes and Definitions ofPain Terms”, 2nd edition, Meskey and Begduk, editors; IASP Press,Seattle, 1994), especially for the treatment of cancer-induced pain andchronic neuropathic pain like, for example, that associated withdiabetic neuropathy, postherpetic neuralgia, peripheral nerve damage,central pain (for example as a consequence of cerebral ischaemia) andtrigeminal neuralgia, and other chronic pain such as, for example,lumbago, backache (low back pain) or rheumatic pain. In addition, theseactive ingredients are also suitable for the therapy of primary acutepain of any origin and of secondary states of pain resulting therefrom,and for the therapy of states of pain which were formerly acute and havebecome chronic. The compounds of the invention can be employed alone orin combination with other active ingredients for the treatment ofschizophrenia.

The in vitro effect of the compounds of the invention can be shown inthe following assays:

1. Determination of the Affinity of Test Substances for α7 nAChR byInhibition of [³H]-Methyllycaconitine Binding to Rat Brain Membranes

The [³H]-methyllycaconitine binding assay is a modification of themethod described by Davies et al. in Neuropharmacol. 1999, 38, 679-690.

Rat brain tissue (hippocampus or whole brain) is homogenized in aqueoushomogenization buffer (10% w/v, 0.32 M sucrose, 1 mM EDTA, 0.1 mMphenylmethylsulfonyl fluoride (PMSF), 0.01% (w/v) NaN₃, pH 7.4, 4° C.)at 600 rpm in a glass homogenizer. The homogenate is centrifuged(1000×g, 4° C., 10 min) and the supernatant is removed. The pellet isresuspended (20% w/v) and the suspension is centrifuged (1000×g, 4° C.,10 min). The two supernatants are combined and centrifuged (15 000×g, 4°C., 30 min). The pellet obtained in this way is referred to as the P2fraction.

The P2 pellet is suspended in binding buffer (50 mM Tris-HCl, 1 mMMgCl₂, 120 mM NaCl, 5 mM KCl, 2 mM CaCl₂, pH 7.4), and the suspension iscentrifuged (15 000×g, 4° C., 30 min), twice.

The residue is resuspended in binding buffer to a concentration of 4mg/ml and incubated in a volume of 250 μl (amount of membrane protein0.4 mg) in the presence of 2 nM [3H]-methyllyeaconitine, 0.1% (w/v) BSA(bovine serum albumin) and various concentrations of the test substanceat 21° C. for 60 min.

Incubation is then carried out in the presence of 1 μM α-bungarotoxin or100 μM nicotine or 10 μM MLA (methyllycaconitine). The incubation isstopped by adding 4 ml of PBS (20 mM Na₂HPO₄, 5 mM KH₂PO₄, 150 mM NaCl,pH 7.4, 4° C.) and filtering through type A/E glass fiber filters(Gelman Sciences) which have previously been placed in 0.3% (v/v)polyethyleneimine (PEI) for 3 h. The filters are washed twice with 4 mlof PBS (4° C.), and the bound radioactivity is determined byscintillation measurement. All the assays are carried out in triplicate.The dissociation constant K_(i) of the test substance was determinedfrom the IC₅₀ of the compounds (concentration of the test substance atwhich 50% of the ligand bound to the receptor is displaced), thedissociation constant K_(D) and the concentration L of[³H]-methyllycaconitine using the equation K_(i)=IC₅₀/(1+L/K_(D)).

In place of [³H]-methyllycaconitine it is also possible to employ otherca nAChR-selective radioligands such as, for example,[¹²⁵I]-α-bungarotoxin or nonselective nAChR radioligands together withinhibitors of other nAChRs.

The in vitro data for the effects of the compounds of the invention showa K_(i) of <300 nM. Representative in vitro data for the effects of thecompounds of the invention are shown in Table A:

TABLE A Example K_(i) (nM) 4 2.1 5 22.0 6 7.9 11 0.4 21 15.0 16 4.3 22<1.00

The assay described below shows that the compounds of the invention haveonly low affinity for 5-HT₃ receptors and thus act selectively onα7-nAChR.

2. Determination of the Affinity of Test Substances for 5-HT₃ ReceptorsThrough Inhibition of [³H]GR65630 Binding

Membranes from HEK293 cells which express recombinant human 5-HT₃receptor (RB-HS3, Receptor Biology, Inc., MD, USA) are diluted inaccordance with the manufacturer's instructions in incubation buffer (50mM Iris base, pH 7.4, 5 mM MgCl₂, 0.5 mM EDTA, 0.1% (w/v) ascorbic acid,10 μM pargyline and incubated in a volume of 200 μl (amount of membraneprotein 3 μg) in the presence of 0.5 nM of the selective 5-HT₃ receptorradio ligand [³H]-GR65630 (NET 1011, Du Pont) and various concentrationsof the test substance at 21° C. for 60 min. The nonspecific binding isdetermined by incubation in the presence of 100 μM 5-HT(5-hydroxytryptamine). The incubation is stopped by filtering throughtype A/E glass fiber filters (Gelman Sciences) or GF/B filters (Whatman)which have previously been placed in 0.3% (v/v) polyethyleneimine (PEI)for at least 1 h. The filters are washed three times with 3 ml ofwashing buffer (50 mM Tris-HCl, pH 7.4; 4° C.), and the boundradioactivity is determined by scintillation measurement. All the assaysare carried out in triplicate. The dissociation constant K_(i) of thetest substance is determined from the IC₅₀ of the compounds(concentration of the test substance at which 50% of the ligand bound tothe receptor is displaced), the dissociation constant K_(D) and theconcentration L of [³H]GR65630 (K_(i)=IC₅₀/(1+L/K_(D))).

TABLE B Example K_(i) (nM) 5 12000 6 1700 11 5500 21 1600 14 6900 162100

The suitability of the compounds of the invention for the treatment ofcognitive impairments can be shown in the following animal models:

3. Object Recognition Test

The object recognition test is a memory test. It measures the ability ofrats (and mice) to distinguish between familiar and unfamiliar objects.

The test is described by Blokland et al., Neuro Report 1998, 9,4205-4208; A. Ennaceur et al., Behav. Brain Res. 1988, 31, 47-59; A.Ennaceur et al., Psychopharmacology 1992, 109, 321-330; and Prickaertset al., Eur. J. Pharmacol. 1997, 337, 125-136.

In a first run, a rat is confronted in an otherwise empty observationarena of relatively large size by two identical objects. The rat willinvestigate, i.e. sniff round and touch, both objects extensively. In asecond run, after an interval of 24 hours, the rat is put in theobservation arena again. One of the familiar objects has now beenreplaced by a new, unfamiliar object. If a rat recognizes the familiarobject, it will concentrate on investigating the unfamiliar object.However, after 24 hours, a rat has normally forgotten which object itinvestigated in the first run, and it will therefore inspect bothobjects to the same extent. Administration of a substance with alearning- and memory-improving effect may lead to a rat recognizing theobject seen in the first run 24 hours previously as familiar. It willinvestigate the new, unfamiliar object in more detail than the familiarone. This memory ability is expressed in a discrimination index. Adiscrimination index of zero means that the rat investigates bothobjects, the old and the new, for equal times; that is to say it has notrecognized the old object and reacts to both objects as if they werenew. A discrimination index greater than zero means that the ratinspects the new object longer than the old one; that is to say the rathas recognized the old object.

4. Social Recognition Test:

The social recognition test is a test to examine the learning- ormemory-improving effect of test substances.

Adult rats housed in groups are placed singly in test cages 30 minutesbefore the start of the test. Four minutes before the start of the test,the test animal is put in an observation box. After this adaptationtime, a juvenile animal is put in with the test animal and the time forwhich the adult animal investigates the juvenile animal is measured for2 minutes (trial 1). All behaviors clearly directed at the young animalare measured, i.e. anogenital inspection, pursuit and grooming, duringwhich the old animal is no further than 1 cm from the young animal. Thejuvenile animal is then taken out, and the adult is left in its testcage (for 24-hour retention, the animal is returned to its home cage).The adult test animal is treated with test substance before or after thefirst test. Depending on the timing of the treatment, the learning orthe storage of the information about the young animal can be influencedby the substance. After a fixed period (retention), the test is repeated(trial 2). A larger difference between the investigation times measuredin trials 1 and 2 means that the adult animal has remembered the younganimal better.

The novel active ingredients can be converted in a known mariner intoconventional formulations such as tablets, coated tablets, pills,granules, aerosols, syrups, emulsions, suspensions and solutions, usinginert, nontoxic, pharmaceutically suitable carriers or solvents. Inthese cases, the therapeutically active compound should in each case bepresent in a concentration of about 0.5 to 90% by weight of theformulation, i.e. in amounts which are sufficient to reach the stateddose range.

The formulations are produced for example by extending the activeingredients with solvents and/or carriers, where appropriate with use ofemulsifiers and/or dispersants, it being possible for example when wateris used as diluent where appropriate to use organic solvents asauxiliary solvents.

Administration takes place in a conventional way, preferably orally,transdermally or parenterally, especially perlingually or intravenously.However, it can also take place by inhalation through the mouth or nose,for example with the aid of a spray, or topically via the skin.

It has generally proved advantageous to administer amounts of about0.001 to 10 mg/kg, on oral administration preferably about 0.005 to 3mg/kg, of body weight to achieve effective results.

It may, nevertheless, be necessary where appropriate to deviate from thestated amounts, in particular as a function of the body weight or of themode of administration, of the individual behavior toward themedicament, the nature of its formulation and the time or interval overwhich administration takes place. Thus, it may be sufficient in somecases to make do with less than the aforementioned minimum amount,whereas in other cases the stated upper limit must be exceeded. Wherelarger amounts are administered, it may be advisable to divide theseinto a plurality of single doses over the day.

Unless indicated otherwise, all quantitative data relate to percentagesby weight. Solvent ratios, dilution ratios and concentration data ofliquid/liquid solutions are based in each case on volume. The statement“w/v” means “weight/volume”. Thus, for example, “10% w/v” means: 100 mlof solution or suspension contain 10 g of substance.

ABBREVIATIONS

-   BINAP 2,2′-Bis-(diphenylphosphino)-1,1′-binaphthyl-   DAD Diode array detector-   DMF N,N-Dimethylformamide-   DMSO Dimethyl sulfoxide-   EDTA Ethylenediaminetetraacetic acid-   eq. Equivalent-   ESI Electrospray ionization (in MS)-   HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HOBt 1-Hydroxy-1H-benzotriazole×H₂O-   HPLC High pressure/high performance liquid chromatography-   LC-MS Coupled liquid chromatography-mass spectroscopy-   MS Mass spectroscopy-   NMR Nuclear magnetic resonance spectroscopy-   PBS Phosphate buffered saline-   Pd₂(dba)₃ Tris(dibenzylideneacetone)dipalladium(0)-   RT Room temperature (20° C.)-   R_(t) Retention time (in HPLC)-   TBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    tetrafluoroborate-   THF Tetrahydrofuran-   Tris Tris-(hydroxymethyl)-aminomethane    HPLC Method:

Instrument: HP 1100 with DAD detection; column: Kromasil RP-18, 60 mm×2mm, 3.5 μm; Eluent: A=5 ml of HClO₄/L of H₂O, B=acetonitrile; gradient:0 min 2% B, 0.5 min 2% B, 4.5 min 90% B, 6.5 min 90% B; flow rate: 0.75mL/min; Temp.: 30° C.; detection: UV 210 nm.

LC-MS Method:

Instrument: Micromass Platform LCZ, HP1100; column. Symmetry C18, 50mm×2.1 mm, 3.5 μm; Eluent A: water+0.05% formic acid, Eluent B:acetonitrile+0.05% formic acid; gradient: 0.0 min 90% A→4.0 min 10%A→6.0 min 10% A; oven: 40° C.; flow rate: 0.5 mL/min; UV detection:208-400 nm.

General Method A Synthesis of 1-benzothiophene-2-carboxylic acids

The appropriate methyl 1-benzothiophene-2-carboxylate is mixed with amixture of equal parts of THF and 2 N aqueous potassium hydroxidesolution (0.28-0.47 M solution). The reaction mixture is left to stir atroom temperature overnight. The THF is removed under reduced pressure,and the aqueous reaction mixture is acidified with concentratedhydrochloric acid. The resulting precipitate is filtered off withsuction and dried in vacuo at 40° C.

General Method B Amide Linkage Between 3-quinuclidinamine and2-benzothiophenecarboxylic acids

1.0 eq. of the appropriate enantiomeric 3-quinuclidinaminehydrochloride, 1.0 eq. of the carboxylic acid and 1.2 eq. of HATU in DMFat 0° C. are stirred after addition of 1.2 eq. ofN,N-diisopropylethylamine for 30 min. Then a further 2.4 eq. ofN,N-diisopropylethylamine are added, and the mixture is stirred at RTovernight.

STARTING COMPOUNDS Example 1A Methyl7-bromo-1-benzothiophene-2-carboxylate

Under an argon atmosphere, 8.2 g (205.7 mmol) of sodium hydride (60% inliquid paraffin) are introduced into 300 ml of absolute DMSO. At roomtemperature, 16.0 g (150.9 mmol) of methyl mercaptoacetate are slowlyadded dropwise to the reaction mixture, which is stirred at roomtemperature until hydrogen evolution ceases (about 15 min). A solutionof 27.8 g (137.1 mmol) of 3-bromo-2-fluorobenzaldehyde in 50 ml ofabsolute DMSO is added at room temperature to the reaction mixture. Thelatter is stirred until the reaction is complete and then poured intoice-water. The resulting precipitate is filtered off with suction anddried in vacuo at 40° C. overnight. 20.57 g of a mixture of the titlecompound and of the corresponding acid (approx. 1:1) are obtained.

Example 2A Methyl 6-bromo-1-benzothiophene-2-carboxylate

Under an argon atmosphere, 1.93 g (48.3 mmol) of sodium hydride (60% inliquid paraffin) are introduced into 60 ml of absolute DMSO. At roomtemperature, 3.76 g (35.5 mmol) of methyl mercaptoacetate are slowlyadded dropwise to the reaction mixture, which is stirred at roomtemperature until hydrogen evolution ceases (about 15 min) A solution of6.54 g (32.2 mmol) of 4-bromo-2-fluorobenzaldehyde and 15 ml of absoluteDMSO are added at room temperature to the reaction mixture. The latteris stirred until the reaction is complete and then poured intoice-water. The resulting precipitate is filtered off with suction anddried in vacuo at 40° C. overnight. 4.06 g (46.4% of theory) of thetitle compound are obtained.

¹H-NMR (200.1 MHz, DMSO-d₆): δ=8.42 (d, 1H), 8.22 (s, 1H), 7.98 (d, 1H),7.65 (dd, 1H), 3.90 (s, 3H)

HPLC: R_(t)=5.3 min

MS (ESIpos): m/z=270 (M⁺), 288 (M+NH₄)⁺, 305 (M+N₂H₇)⁺

Example 3A Methyl 6-nitro-1-benzothiophene-2-carboxylate

2 g (10.2 mmol) of 2,4-dinitrobenzaldehyde, 1.08 g (10.2 mmol) of methylmercaptoacetate and 2.84 ml (20.4 mmol) of triethylamine aresuccessively dissolved in 6 ml of DMSO. The reaction solution is heatedat 80° C. for 1 h and then poured into 200 ml of ice-water. Severaldichloromethane extractions are carried out. The combined organic phasesare dried over sodium sulfate and concentrated in vacuo. Chromatography(mobile phase: dichloromethane) on silica gel affords 1.12 g (46.1% oftheory) of the title compound.

¹H-NMR (300 MHz, CDCl₃): δ=8.80 (d, 1H), 8.27 (dd, 1H), 8.13 (s, 1H),8.00 (d, 1H), 3.99 (s, 3H)

HPLC: R_(t)=4.7 min

MS (ESIpos): m/z=255 (M+NH₄)⁺

Example 4A 6-Bromo-1-benzothiophene-2-carboxylic acid

3.55 g (93.5% of theory) of the desired product are obtained from 4.0 g(14.8 mmol) of methyl 6-bromo-1-benzothiophene-2-carboxylate by generalmethod A.

¹H-NMR (400.1 MHz, DMSO-d₆): δ=13.48 (s, 1H, br), 8.38 (s, 1H), 8.22 (s,1H), 7.96 (d, 1H), 7.63 (m, 1H)

HPLC: R_(t)=4.5 min.

Example 5A 7-Bromo-1-benzothiophene-2-carboxylic acid

8.99 g (91.0% of theory) of the desired product are obtained from 10.0 g(36.9 mmol) of methyl 7-bromo-1-benzothiophene-2-carboxylate by generalmethod A.

¹H-NMR (200.1 MHz, DMSO-d₆): δ=13.76 (s, 11-1, br), 8.28 (s, 1H), 8.07(d, 1H), 7.78 (d, 1H), 7.46 (dd, 1H)

HPLC: 99.1%, R_(t)=4.4 min.

Example 6A 6-Nitro-1-benzothiophene-2-carboxylic acid

1.20 g (91.4% of theory) of the desired product are obtained from 1.4 g(5.90 mmol) of methyl 6-nitro-1-benzothiophene-2-carboxylate by generalmethod A.

¹H-NMR (200.1 MHz, DMSO-d₆): δ=8.91 (d, 1H), 8.14 (dd, 1H), 8.02 (d,1H), 7.69 (s, 1H)

HPLC: R_(t)=4.1 min

MS (ESIpos): m/z=241 (M+NH₄)⁺

Example 7A 6-[(tert-Butoxycarbonyl)amino]-1-benzothiophene-2-carboxylicacid

400 mg (2.07 mmol) of 6-amino-1-benzothiophene-2-carboxylic acid and1.36 g (6.21 mmol) of di-tert-butyl pyrocarbonate are stirred in amixture of 5 ml of dioxane and 10 ml of aqueous 1 N sodium bicarbonatesolution at room temperature for 18 h. The solution is adjusted to pH5-6 with 10% strength aqueous citric acid solution and extracted fourtimes with ethyl acetate. The combined organic phases are dried oversodium sulfate and concentrated. The residue is chromatographed onsilica gel (mobile phase: dichloromethane/methanol). 214 mg (30% oftheory) of the title compound are obtained.

MS (ESIpos): m/z=316 (M+Na)⁺

Example 8AN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamidehydrochloride

903.8 mg (3.52 mmol) of 7-bromo-1-benzothiophene-2-carboxylic acid,700.0 mg (3.52 mmol) of R-aminoquinulidine dihydrochloride; 1604.0 mg(4.22 mind) of HATU, 1635.7 mg (12.66 mmol) of N,N-diisopropylethylamineand 7.0 ml of DMF are reacted by general method B. The reaction mixtureis purified by preparative HPLC. The product is dissolved in a 1:1mixture of 4 M HCl in dioxane and 1 N hydrochloric acid and thenconcentrated and dried under high vacuum. 1087 mg (77% of theory) of thetitle compound are obtained.

¹H-NMR (200.1 MHz, DMSO-d₆): δ=10.01 (s, 1H, br), 9.15 (d, 1H), 8.47 (s,1H), 8.02 (m, 1H), 7.74 (m, 1H), 7.43 (dd, 1H), 4.34 (m, 1H), 3.80-3.10(m, 6H), 2.22 (m, 1H), 2.14 (m, 1H), 1.93 (In, 2H), 1.78 (m, 1H)

HPLC: R_(t)=4.1 min

MS (ESIpos): m/z=367 (M+H, ⁸¹Br)⁺, 365 (M+H, ⁷⁹Br)⁺

Example 9AN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamidehydrochloride

900.0 mg (3.50 mmol) of 4-bromo-1-benzothiophene-2-carboxylic acid,697.0 mg (3.50 mmol) of R-aminoquinuclidine dihydrochloride, 1597.1 mg(4.20 mmol) of HATU, 1628.7 mg (12.60 mmol) of N,N-diisopropylethylamineand 8.0 ml of DMF are reacted by general method 13. The reaction mixtureis purified by preparative HPLC. The product is dissolved in a 1:1mixture of 4 M HCl in dioxane and 1 N hydrochloric acid and thenconcentrated. Recrystallization from methanol/ethanol (1:10) yields 594mg (42.1% of theory) of the title compound.

¹H-NMR (300.1 MHz, DMSO-d₆): δ=9.81 (s, 1H, br), 8.76 (m, 1H), 8.33 (s,1H), 8.22 (s, 1H), 7.91 (d, HD, 7.59 (dd, 1H), 4.15 (m, 1H), 3.51-2.93(m, 6H), 2.12-1.92 (m, 2H), 1.79 (m, 2H), 1.58 (m, 1H)

HPLC: R_(t)=4.1 min

MS (ESIpos): m/z=366 (M, ⁸¹Br)⁺, 364 (M, ⁷⁹Br)⁺

Example 10AN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1-benzothiophene-2-carboxamidehydrochloride

290.0 mg (1.30 mmol) of 6-nitro-1-benzothiophene-2-carboxylic acid,258.7 nag (1.30 mmol) of R-aminoquinuclidine dihydrochloride, 592.8 mg(1.56 mmol) of HATU, 604.5 mg (4.68 mmol) of N,N-diisopropylethylamineand 2.0 ml of DMF are reacted by general method B. The reaction mixtureis purified by preparative HPLC, mixed with 1 N hydrochloric acid andthen concentrated. Recrystallization from isopropanol yields 297 mg(62.1% of theory) of the title compound.

¹H-NMR (400 MHz, MeOD-d₄): δ=8.95 (s, 1H), 8.28 (dd, 1H), 8.20 (s, 1H),811 (d, 1H), 4.46 (m, 1H), 3.87 (m, 1H), 3.52-3.22 (m, 5H), 2.40 (m,1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.98 (m, 1H)

HPLC: R_(t)=3.8 min.

MS (ESIpos): m/z=332 (M+H)⁺.

Example 11AN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-7-amino-1-benzothiophene-2-carboxamidedihydrochloride

87 mg (0.22 mmol) ofN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-3-bromo-1-benzothiophene-2-carboxamidehydrochloride, 47.1 mg (0.26 mmol) of benzophenone imine, 12.1 mg (0.02mmol) of rac-BINAP, 45.8 mg (0.48 mmol) of sodium tert-butoxide and 6.0mg (0.01 mmol) of Pd₂(dba)₃ are put under argon in a heat-dried flask.1.5 ml of toluene are added, and the reaction mixture is heated to 80°C. After 30 min, 0.5 ml of THF, and after 6 h a further 6.0 mg (0.01mmol) of Pd₂(dba)₃, are added. After a further 6 h, a filtration (0.45μm filter) is followed by purification by preparative HPLC. Theresulting benzophenone imine adduct is dissolved in a 1:1 mixture of THFand methanol with the addition of 20% by volume 1 N hydrochloric acid.After 1 h at room temperature, the reaction mixture is concentrated. Theresulting solid is stirred with acetonitrile and filtered. Drying underhigh vacuum results in 17 mg (21% of theory) of the title compound.

¹H-NMR (400.1 MHz, D₂O): δ=8.11 (s, 1H), 7.89 (d, 1H), 7.53 (dd, 1H),7.37 (d, 1H), 4.48 (m, 1H), 3.87 (m, 1H), 3.52-3.30 (m, 5H), 2.44 (m,1H), 2.27 (m, 114), 2.12 (m, 2H), 2.00 (m, 1H)

HPLC: R_(t)=2.9 min

MS (ESIpos): m/z=302 (M+H)⁺

Example 12A6-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride

Method A):

15 mg (0.05 mmol) of6-[(tert-butoxycarbonyl)amino]-1-benzothiophene-2-carboxylic acid, 10.2mg (0.05 mmol) of R-aminoquinuclidine dihydrochloride, 21.4 mg (0.06mmol) of HATU, 21.8 mg (0.17 mmol) of N,N-diisopropylethylamine and 1 mlof DMF are reacted by general method B. The reaction mixture is purifiedby preparative HPLC. The product is mixed with 5 ml of 4 M HCl indioxane and stirred at room temperature for 30 min. A mixture isconcentrated and dried under high vacuum. 17 mg (98% of theory) of thetitle compound are obtained.

Method B):

247 mg (0.67 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-nitro-1-benzothiophene-2-carboxamidehydrochloride are suspended in 1.6 ml of 1 N hydrochloric acid and 4.3ml of methanol and, under argon, 25.6 mg of palladium on carbon (5%) areadded. The mixture is stirred under a hydrogen atmosphere (atmosphericpressure) for 2 h. The contents of the flask are filtered throughkieselguhr and evaporated to dryness in vacuo. 241 mg (95.6% of theory)of the title compound are obtained.

Method C):

10 ml of a 1:1 mixture of THF and toluene are added to a mixture of 730mg (1.76 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-bromo-1-benzothiophene-2-carboxamidehydrochloride, 638.9 mg (3.53 mmol) of benzophenone imine, 109.8 mg(0.18 mmol) of rac-BINAP, 508.2 mg (5.29 mmol) of sodium tert-butoxideand 161.4 mg (0.18 mmol) of Pd₂(dba)₃, and the reaction mixture isheated at 85° C. overnight. The contents of the flask are concentratedto about 7 ml and purified by preparative HPLC. The resultingbenzophenone imine adduct is dissolved in a mixture of 5 ml of methanoland 3 ml of 1 N hydrochloric acid and stirred at room temperature for 1h. Concentration of the solution is followed by recrystallization frommethanol/diethyl ether and further purification by preparative HPLC. Theproduct fractions are mixed with 1 N of hydrochloric acid. Concentrationand drying under high vacuum result in 67 mg (10.1% of theory) of thetitle compound.

¹H-NMR (400.1 MHz, D₂O): δ=7.95 (m, 2H), 7.88 (m, 1H), 7.32 (m, 1H),4.37 (m, 1H), 3.80-3.69 (m, 2H), 3.40-3.18 (m, 4H), 2.32 (m, 1H), 2.16(m, 1H), 2.00 (m, 2H), 1.89 (m, 1H)

HPLC: R_(t)=2.7 min

MS (ESIpos): m/z=302 (M+H)⁺

Example 13A 2-(Hydroxymethyl)-5-nitrophenol

10.0 g (54.6 mmol) of 4-nitrosalicylic acid are introduced into 100 mlof THF. While cooling in ice, 109 nil of 1 M borane-THF complex areadded, and the mixture is stirred at room temperature overnight. It isconcentrated and the precipitate is filtered off with suction. The solidis dissolved in ethyl acetate and dried over magnesium sulfate. Afterconcentration and drying under high vacuum, the title compound isimmediately reacted further.

LC-MS (ESIpos): m/z=169 (M⁺)

Example 14A 2-Hydroxy-4-nitrobenzaldehyde

6.0 g (35.5 mmol) of 2-(hydroxymethyl)-5-nitrophenol and 3.1 g (35.5mmol) of activated manganese(IV) oxide in 100 ml of chloroform areheated under reflux for 20 h. The mixture is filtered throughkieselguhr, concentrated and dried under high vacuum. The title compoundis immediately reacted further.

MS (ESIpos): m/z=167 (M⁺)

Example 15A 6-Nitro-1-benzofuran-2-carboxylic acid

5.8 g (34.7 mmol) of 2-hydroxy-4-nitrobenzaldehyde, 1.28 g (3.5 mmol) oftetrabutylammonium iodide and 19.2 g (138.8 mmol) of potassium carbonateare mixed, 7.9 g (72.9 mmol) of methyl chloroacetate are added, and themixture is heated at 130° C. for 12 h. 100 ml of THF are added and,while cooling in ice, 11.7 g (208.2 mmol) of potassium hydroxide areadded. Addition of 100 ml of water is followed by stirring at roomtemperature for 20 h. The pH is adjusted to pH 1 with conc. hydrochloricacid. The mixture is extracted with ethyl acetate. The organic phase iswashed with water and dried over sodium sulfate. Addition of silica gelis followed by concentration and chromatography on silica gel (mobilephase: toluene/methanol/acetic acid). Concentration of the productfractions and drying in vacuo result in 1.31 g (18.2% of theory) of thetitle compound.

HPLC: R_(t)=3.8 min

MS (ESIpos): m/z=225 (M+NH₄)⁺

Example 16AN-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-nitro-1-benzofuran-2-carboxamide

1.3 g (5.02 mmol) of 6-nitro-1-benzofuran-2-carboxylic acid, 1.0 g (5.02mmol) of R-aminoquinuclidine dihydrochloride, 2.29 g (6.02 mmol) ofHATU, 2.34 g (18.07 mmol) of N,N-diisopropylethylamine and 10 ml of DMFare reacted by general method B. The mixture is concentrated in vacuoand extracted with 1 N sodium hydroxide solution and with ethyl acetate,the organic phase is dried over sodium sulfate and concentrated, and theresidue is dissolved in methanol. Dowex 50WX2-200 ion exchanger resin isadded, and within 1 h, the mixture is concentrated in a rotaryevaporator. The resin is washed successively with methanol, DMF,methanol, THF, methanol, dichloromethane, methanol and 10% triethylaminein methanol. The product fraction is concentrated. 1.75 g (99% oftheory) of the title compound are obtained.

HPLC: R_(t)=3.6 min.

MS (ESIpos): m/z=316 (M+H)⁺

Example 17A6-Amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamide

1.55 g (4.92 mmol) ofN-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-6-nitro-1-benzofuran-2-carboxamideare dissolved in 15 ml of 2 M tin(II) chloride solution in DMF andstirred at room temperature overnight. Dowex 50WX2-200 ion exchangerresin is added and, within 1 h, the mixture is concentrated in a rotaryevaporator. The resin is washed successively with water, DMF, methanol,dichloromethane, methanol and 10% triethylamine in methanol. The productfraction is concentrated and chromatographed on silica gel (mobilephase: dichloromethane/methanol/triethylamine). Concentration in vacuoresults in 642.8 mg (45.8% of theory) of the title compound.

HPLC: R_(t)=2.6 min

MS (ESIpos): m/z=286 (M+H)⁺.

EXEMPLARY EMBODIMENTS Example 1 6-[(Anilinocarbonyl)amino]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidehydrochloride

A solution of 80 mg (0.21 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 4 ml of THF is mixed with 59.6 μl (0.43 mmol) oftriethylamine and 50.9 mg (0.43 mmol) of phenyl isocyanate. After 16 hat room temperature, the reaction mixture is purified by preparativeHPLC. The concentrated product fraction is dissolved in a mixture ofacetonitrile and 1 N hydrochloric acid (5:1), again concentrated anddried under high vacuum. 35 mg (35.8% of theory) of the title compoundare obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.21 (s, 1H), 8.00 (s, 114), 7.82 (d,1H), 7.45 (m, 2H), 7.38 (dd, 1H), 7.30 (m, 2H), 7.03 (dd, 1H), 4.43 (pa,1H), 3.85 (m, 1H), 3.52-3.20 (m, 5H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10(m, 2H), 1.96 (m, 1H)

HPLC: R_(t)=3.9 min.

MS (ESIpos): m/z=421 (M+H)⁺ (free base).

Example 2N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-chlorophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) oftriethylamine and 32.8 mg (0.21 mmol) of 4-chlorophenyl isocyanate.After 16 h at room temperature, the mixture is concentrated in vacuo.The residue is dissolved in a 1:1 mixture of water and acetonitrile andpurified by preparative HPLC. The concentrated product fraction isdissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1),again concentrated and dried under high vacuum. 29 mg (55.2% of theory)of the title compound are obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.21 (s, 1H), 8.02 (s, 1H), 7.82 (d,1H), 7.47 (m, 2H), 7.38 (dd, 1H), 7.29 (m, 2H), 4.44 (m, 1H), 3.85 (m,1H), 3.52-3.12 (m, 5H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96(m, 1H) HPLC: R_(t)=4.1 min.

MS (ESIpos): m/z=455 (M+H)⁺ (free base).

Example 3N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-methoxyphenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 80 mg (0.21 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 4 ml of THF is mixed with 59.6 μl (0.43 mmol) oftriethylamine and 63.8 mg (0.43 mmol) of 2-methoxyphenyl isocyanate.After 16 h at room temperature, the product is purified by preparativeHPLC. The concentrated product fraction is dissolved in a mixture ofacetonitrile and 1 N hydrochloric acid (5:1), again concentrated anddried under high vacuum. 10 mg (9.6% of theory) of the title compoundare obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.23 (s, 1H), 8.09 (d, 1H), 8.03 (s,1H), 7.82 (d, 1H), 7.36 (m, 1H), 7.00 (m, 2H), 6.92 (m, 1H), 4.44 (m,1H), 3.93 (s, 3H), 3.84 (m, 1H), 3.48 (m, 1H), 3.42-3.25 (m, 4H), 2.39(m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H)

HPLC: R_(t)=4.0 min.

MS (ESIpos): m/z=451 (M+H)⁺ (free base).

Example 4N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methoxyphenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 80 mg (0.21 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 4 ml of THF is mixed with 59.6 μl (0.43 mmol) oftriethylamine and 63.8 mg (0.43 mmol) of 4-methoxyphenyl isocyanate.After 16 h at room temperature, the product is purified by preparativeHPLC. The concentrated product fraction is dissolved in a mixture ofacetonitrile and 1 N hydrochloric acid (5:1), again concentrated anddried under high vacuum. 55 mg (52.8% of theory) of the title compoundare obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.20 (s, 1H), 8.00 (s, 1H), 7.81 (d,1H), 7.35 (m, 3H), 6.89 (m, 2H), 4.44 (m, 1H), 3.85 (m, 1H), 3.78 (s,3H), 3.52-3.22 (m, 5H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96(m, 1H)

HPLC: R_(t)=3.8 min.

MS (ESIpos): m/z=451 (M+H)⁺ (free base).

Example 5N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-phenylethyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) oftriethylamine and 31.5 mg (0.21 mmol) of (2-isocyanatoethyl)benzene.After 18 h at room temperature, the product is purified by preparativeHPLC. The concentrated product fraction is dissolved in a mixture ofacetonitrile and 1 N hydrochloric acid (5:1), again concentrated anddried under high vacuum. 32 mg (61.8% of theory) of the title compoundare obtained.

¹H-NMR (400 MHz, Methanol-d_(i)): δ=8.11 (s, 1H), 8.02 (s, 1H), 7.77 (d,1H), 7.36-7.16 (m, 6H), 4.44 (m, 1H), 3.83 (m, 1H), 3.55-3.23 (m, 7H),2.86 (tr, 2H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96 (m, 1H)

HPLC: R_(t)=4.0 min.

MS (ESIpos): m/z=449 (M+H)⁺ (free base).

Example 6N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) oftriethylamine and 30.8 mg (0.21 mmol) of 3-cyanophenyl isocyanate. After18 h at room temperature, the product is purified by preparative HPLC.The concentrated product fraction is dissolved in a mixture ofacetonitrile and 1 N hydrochloric acid (5:1), again concentrated anddried under high vacuum. 32 mg (62.1% of theory) of the title compoundare obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.23 (s, 1H), 8.00 (m, 2H), 7.83 (d,1H), 7.67 (d, 1H), 7.47 (dd, 1H), 7.39 (m, 2H), 4.43 (m, 1H), 3.86 (m,1H), 3.53-3.18 (m, 5H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.97(m, 1H).

HPLC: R_(t)—-3.9 min.

MS (ESIpos): 446 (M+H)⁺ (free base).

Example 7N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-bromophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) oftriethylamine and 42.3 mg (0.21 mmol) of 3-bromophenyl isocyanate. After18 h at room temperature, the product is purified by preparative HPLC.The concentrated product fraction is dissolved in a mixture ofacetonitrile and 1 N hydrochloric acid (5:1), again concentrated anddried under high vacuum. 43 mg (75.1% of theory) of the title compoundare obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.21 (s, 1H), 8.02 (m, 1H), 7.82 (m,2H), 7.37 (m, 2H), 7.19 (m, 2H), 4.45 (m, 1H), 3.84 (m, 1H), 3.54-3.20(m, 5H), 2.39 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.97 (m, 1H)

HPLC: R_(t)=4.2 min.

MS (ESIpos): m/z=499 (M+H)⁺ (free base).

Example 8N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-ethoxyphenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THE is mixed with 29.8 μl (0.21 mmol) oftriethylamine and 34.9 mg (0.21 mmol) of 2-ethoxyphenyl isocyanate.After 18 h at room temperature, the product is purified by preparativeHPLC. The concentrated product fraction is dissolved in a mixture ofacetonitrile and 1 N hydrochloric acid (5:1), again concentrated anddried under high vacuum. 10 mg (18.7% of theory) of the title compoundare obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.25 (s, 1H), 8.09 (d, 1H), 8.00 (s,1H), 7.82 (d, 1H), 7.38 (d, 1H), 6.98 (m, 2H), 6.91 (m, 1H), 4.43 (m,1H), 4.16 (q, 2H), 3.86 (m, 1H), 3.53-3.21 (m, 5H), 2.39 (m, 1H), 2.28(m, 1H), 2.10 (m, 2H), 1.97 (tn, 1H), 1.50 (tr, 3H)

HPLC: =4.2 min.

MS (ESIpos): m/z=465 (M+H)⁺ (free base).

Example 9N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-(dimethylamino)phenyl)amino]-carbonyl}amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) oftriethylamine and 34.7 mg (0.21 mmol) of 4-N,N-dimethylaminophenylisocyanate. After 18 h at room temperature, the product is purified bypreparative HPLC. The concentrated product fraction is dissolved in amixture of acetonitrile and 1 N hydrochloric acid (5:1), againconcentrated and dried under high vacuum. 21 mg (38.7% of theory) of thetitle compound are obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.24 (s, 1H), 8.05 (s, 1H), 7.84 (d,1H), 7.72 (m, 2H), 7.58 (m, 2H), 7.39 (d, 1H), 4.45 (m, 1H), 3.84 (m,1H), 3.53-3.20 (m, 11H), 2.39 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.97(m, 1H)

HPLC: R₄=3.3 rain.

MS (ESIpos): m/z=464 (M+H)⁺ (free base).

Example 10N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-nitrophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) oftriethylamine and 35.1 mg (0.21 mmol) of 2-nitrophenyl isocyanate. After18 h at room temperature, the product is purified by preparative HPLC.The concentrated product fraction is dissolved in a mixture ofacetonitrile and 1 N hydrochloric acid (5:1), again concentrated anddried under high vacuum. 6 mg (11.2% of theory) of the title compoundare obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.51 (d, 1H), 8.30 (s, 1H), 8.20 (d,1H), 8.01 (s, 1H), 7.85 (d, 1H), 7.69 (dd, 1H), 7.45 (d, 1H), 7.20 (dd,1H), 4.45 (m, 1H), 186 (m, 1H), 3.52-3.10 (m, 5H), 2.39 (m, 1H), 2.28(m, 1H), 2.11 (m, 2H), 1.97 (m, 1H)

HPLC: R_(t)=4.1 min.

MS (ESIpos): m/z=466 (M+H)⁺ (free base).

Example 11N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,6-difluorophenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) oftriethylamine and 33.2 mg (0.21 mmol) of 2,6-difluorophenyl isocyanate.After 18 h at room temperature, the product is purified by preparativeHPLC. The concentrated product fraction is dissolved in a mixture ofacetonitrile and 1 N hydrochloric acid (5:1), again concentrated anddried under high vacuum. 40 mg (75.9% of theory) of the title compoundare obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.18 (s, 1H), 8.01 (s, 1H), 7.83 (d,1H), 7.41 (d, 1H), 7.30 (m, 1H), 7.06 (m, 2H), 4.43 (m, 1H), 3.85 (m,1H), 3.52-3.22 (m, 5H), 2.39 (m, 1H), 2.28 (m, 1H), 2.11 (m, 2H), 1.97(m, 1H)

HPLC: R_(t)=3.8 min.

MS (ESIpos): m/z=457 (M+H)⁺ (free base).

Example 12N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,4-dichlorophenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) oftriethylamine and 40.2 mg (0.21 mmol) of 2,4-dichlorophenyl isocyanate.After 18 h at room temperature, the product is purified by preparativeHPLC. The concentrated product fraction is dissolved in a mixture ofacetonitrile and 1 N hydrochloric acid (5:1), again concentrated anddried under high vacuum. 25 mg (44.5% of theory) of the title compoundare obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.26 (s, 1H), 8.19 (d, 1H), 8.01 (s,1H), 7.83 (d, 1H), 7.49 (m, 1H), 7.38 (d, 1H), 7.31 (d, 1H), 4.43 (m,1H), 3.85 (m, 1H), 3.51-3.18 (m, 5H), 2.38 (m, 1H), 2.27 (m, 1H), 2.10(m, 2H), 1.96 (m, 1H)

HPLC: R_(t)=4.4 min.

MS (ESIpos): m/z=489 (M+H)⁺ (free base).

Example 13N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-(trifluoromethyl)phenyl]amino}-carbonyl)amino]-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THE is mixed with 29.8 μl (0.21 mmol) oftriethylamine and 40.0 mg (0.21 mmol) of 3-trifluoromethylphenylisocyanate. After 18 h at room temperature, the product is purified bypreparative HPLC. The concentrated product fraction is dissolved in amixture of acetonitrile and 1 N hydrochloric acid (5:1), againconcentrated and dried under high vacuum. 51 mg (89% of theory) of thetitle compound are obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.22 (s, 1H), 8.04 (s, 1H), 7.93 (s,1H), 7.83 (d, 1H), 7.63 (d, 1H), 7.49 (dd, 1H), 7.40 (m, 1H), 7.31 (d,1H), 4.44 (m, 1H), 3.84 (m, 1H), 3.54-3.25 (m, 5H), 2.38 (m, 1H), 2.28(m, 1H), 2.10 (m, 2H), 1.97 (m, 1H)

HPLC: R_(t)=4.3 min.

MS (ESIpos): m/z=489 (M+H)⁺ (free base).

Example 14N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4,5-trimethoxyphenyl)amino]-carbonyl}amino)-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF is mixed with 29.8 μl (0.21 mmol) oftriethylamine and 44.7 mg (0.21 mmol) of 3,4,5-trimethoxyphenylisocyanate. After 18 h at room temperature, the product is purified bypreparative HPLC. The concentrated product fraction is dissolved in amixture of acetonitrile and 1 N hydrochloric acid (5:1), againconcentrated and dried under high vacuum. 11 mg (17.4% of theory) of thetitle compound are obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.22 (s, 1H), 8.00 (s, 1H), 7.82 (d,1H), 7.38 (d, 1H), 6.82 (s, 2H), 4.43 (m, 1H), 3.85 (m, 7H), 3.73 (s,3H), 3.52-3.18 (m, 5H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96(m, 1H)

HPLC: R_(t)=3.8 min.

MS (ESIpos): m/z=511 (M+H)⁺ (free base).

Example 15N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[4-methoxy-3-(trifluoromethyl)phenyl]-amino}carbonyl)amino]-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8(0.21 mmol) of triethylamine and 46.4 mg (0.21 mmol) of4-methoxy-3-trifluoromethylphenyl isocyanate. After 18 h at roomtemperature, the product is purified by preparative HPLC. Theconcentrated product fraction is dissolved in a mixture of methanol and1 N hydrochloric acid (2:1), again concentrated and dried under highvacuum. 15 mg (25.3% of theory) of the title compound are obtained.

¹H-NMR (300 MHz, Methanol-d₄): δ=8.18 (d, 1H), 8.02 (s, 1H), 7.81 (d,1H), 7.73 (d, 1H), 7.60 (dd, 1H), 7.37 (dd, 1H), 7.13 (d, 1H), 4.43 (m,1H), 3.87 (a, 3H), 3.83 (m, 1H), 3.53-3.17 (m, 5H), 2.38 (m, 1H), 2.27(m, 1H), 2.10 (m, 2H), 1.96 (m, 1H)

HPLC: R_(t)=4.2 min.

MS (ESIpos): m/z=519 (M+H)⁺ (free base).

Example 16N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-methoxyphenyl]amino}carbonyl)-amino]-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl(0.21 mmol) of triethylamine and 31.9 mg (0.21 mmol) of 3-methoxyphenylisocyanate. After 18 h at room temperature, the product is purified bypreparative HPLC. The concentrated product fraction is dissolved in amixture of methanol and 1 N hydrochloric acid (2:1), again concentratedand dried under high vacuum. 17 mg (32.7% of theory) of the titlecompound are obtained.

¹H-NMR (300 MHz, Methanol-d₄): δ=8.20 (d, 1H), 8.02 (s, 1H), 7.81 (d,1H), 7.37 (dd, 1H), 7.08 (m, 2H), 6.93 (m, 1H), 6.61 (m, 1H), 4.43 (m,1H), 3.83 (m, 1H), 3.79 (s, 3H), 3.53-3.15 (m, 5H), 2.38 (m, 1H), 2.27(m, 1H), 2.10 (m, 2H), 1.95 (m, 1H)

HPLC: R_(t)=4.0 min.

MS (ESIpos): m/z=451 (M+H)⁺ (free base).

Example 17N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-trifluoromethoxyphenyl]amino}-carbonyl)amino]-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl(0.21 mmol) of triethylamine and 43.4 mg (0.21 mmol) of3-trifluoromethoxyphenyl isocyanate. After 18 h at room temperature, theproduct is purified by preparative HPLC. The concentrated productfraction is dissolved in a mixture of methanol and 1 N hydrochloric acid(2:1), again concentrated and dried under high vacuum. 8.5 mg (14.7% oftheory) of the title compound are obtained.

¹H-NMR (300 MHz, Methanol-d₄): δ=8.21 (d, 1H), 8.01 (s, 1H), 7.83 (d,1H), 7.62 (s, 1H), 7.85 (m, 3H), 6.92 (m, 1H), 4.45 (m, 1H), 3.84 (m,1H), 3.56-3.06 (m, 5H), 2.38 (m, 1H), 2.28 (m, 1H), 2.10 (m, 2H), 1.96(m, 1H)

HPLC: R_(t)=4.4 min.

MS (ESIpos): m/z=505 (M+H)⁺ (free base).

Example 18N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)carbonyl]amino}-1-benzothiophene-2-carboxamidehydrochloride

A solution of 50 mg (0.13 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 37.2 μl(0.27 mmol) of triethylamine and 26.5 mg (0.27 mmol) of tert-butylisocyanate. After 18 h at room temperature, the product is purified bypreparative HPLC. The concentrated product fraction is dissolved in amixture of acetonitrile and 1 N hydrochloric acid (5:1), againconcentrated and dried under high vacuum. 19 mg (32.6% of theory) of thetitle compound are obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.08 (m, 1H), 7.98 (s, 7.75 (d, 1H),7.23 (dd, 1H), 4.43 (m, 1H), 3.83 (m, 1H), 3.50-3.18 (m, 5H), 2.38 (m,1H), 2.27 (m, 1H), 2.10 (m, 2H), 1.95 (m, 1H), 1.38 (m, 9H)

HPLC: R_(t)=3.8 min.

MS (ESIpos): m/z=401 (M+H)⁺ (free base).

Example 19N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclohexylamino)carbonyl]amino}-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl(0.21 mmol) of triethylamine and 26.8 mg (0.21 mmol) of cyclohexylisocyanate. After 18 h at room temperature, the product is purified bypreparative HPLC. The concentrated product fraction is dissolved in amixture of methanol and 1 N hydrochloric acid (2:1), again concentratedand dried under high vacuum. 23.4 mg (47.3% of theory) of the titlecompound are obtained.

¹H-NMR (300 MHz, Methanol-d₄): δ=8.10 (d, 1H), 7.99 (s, 1H), 7.77 (d,1H), 7.27 (dd, 1H), 4.43 (m, 1H), 3.82 (m, 1H), 3.64-3.10 (m, 6H), 2.37(m, 1H), 2.28 (m, 1H), 2.09 (m, 2H), 1.94 (m, 3H), 1.76 (m, 2H), 1.62(m, 1H), 1.40 (m, 2H), 1.26 (m, 3H)

HPLC: R_(t)=4.0 min.

MS (ESIpos): m/z=427 (M+H)⁺ (free base).

Example 20N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[(1S)-1-phenylethyl]amino}carbonyl)-amino]-1-benzothiophene-2-carboxamidehydrochloride

A solution of 40 mg (0.11 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl(0.21 mmol) of triethylamine and 31.5 mg (0.21 mmol) of(S)-(−)-α-methylbenzyl isocyanate. After 18 h at room temperature, theproduct is purified by preparative HPLC. The concentrated productfraction is dissolved in a mixture of methanol and 1 N hydrochloric acid(2:1), again concentrated and dried under high vacuum. 32.5 mg (62.7% oftheory) of the title compound are obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.10 (s, 1H), 7.99 (m, 2H), 7.77 (d,1H), 7.39-7.20 (m, 5H), 4.93 (q, 1H), 4.43 (m, 1H), 3.83 (m, 1H), 3.47(m, 1H), 3.42-3.26 (m, 4H), 2.37 (m, 1H), 2.27 (m, 1H), 2.09 (m, 2H),1.95 (m, 1H), 1.49 (d, 31-1)

HPLC: R_(t)=4.0 min.

MS (ESIpos): m/z=449 (M+H)⁺ (free base).

Example 217-[(Anilinocarbonyl)amino]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidehydrochloride

A solution of 44 mg (0.12 mmol) of7-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamidedihydrochloride in 2 ml of THF is mixed with 32.8 μl (0.24 mmol) oftriethylamine and 28 mg (0.24 mmol) of phenyl isocyanate. After 18 h atroom temperature, the product is purified by preparative HPLC. Theconcentrated product fraction is dissolved in a mixture of acetonitrileand 1 N hydrochloric acid (5:1), again concentrated and dried under highvacuum. 20 mg (36.1% of theory) of the title compound are obtained.

¹H-NMR (400 MHz, Methanol-d₄): δ=8.12 (s, 1H), 7.80 (d, 1H), 7.70 (d,1H), 7.47 (m, 3H), 7.30 (m, 2H), 7.05 (m, 1H), 4.45 (m, 1H), 3.84 (m,1H), 3.73 (s, 3H), 3.53-3.21 (m, 5H), 2.39 (m, 1H), 2.28 (m, 1H), 2.10(m, 2H), 1.96 (m, 1H)

HPLC: R_(t)=3.9 min.

MS (ESIpos): m/z=421 (M+H)⁺ (free base).

Example 22N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methoxyphenyl)amino]carbonyl}-amino)-1-benzofuran-2-carboxamidehydrochloride

50 mg (0.18 mmol) of6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzofuran-2-carboxamideare introduced into 3 ml of THF/DMF (10:1), and 73 μl (0.53 mmol) oftriethylamine and 78.4 mg (0.53 mmol) of 4-methoxyphenyl isocyanate areadded. After 18 h at room temperature and a further 20 h at 50° C., thecontents of the flask are concentrated in vacuo. After redissolving in alittle DMSO and adding water, the resulting precipitate is filtered offwith suction. The solid is dissolved in DMF/water and purified bypreparative HPLC. The concentrated product fraction is dissolved in amixture of methanol and 1 N hydrochloric acid in diethyl ether (5:1),again concentrated and dried under high vacuum. 5.3 mg (7% of theory) ofthe title compound are obtained.

¹H-NMR (300 MHz, Methanol-d₄): δ=8.07 (s, 1H), 7.60 (m, 1H), 7.47 (s,1H), 7.33 (tn, 2H), 7.12 (dd, 1H), 6.88 (m, 2H), 4.49 (m, 1H), 3.82 (m,1H), 3.77 (s, 3H), 3.54-3.18 (m, 5H), 2.37 (m, 1H), 2.25 (m, 1H), 2.10(m, 2H), 1.96 (m, 1H)

HPLC: R_(t)=3.8 min.

MS (ESIpos): m/z=435 (M+H)⁺ (free base).

The invention claimed is:
 1. A pharmaceutical composition, comprising acompound represented by formula (I):

wherein: R¹ represents 1-azabicyclo[2.2.2]oct-3-yl; R² representshydrogen or C₁-C₆-alkyl; R³ represents hydrogen, halogen, amino, hydroxyor C₁-C₆-alkyl; R⁴ represents hydrogen or C₁-C₆-alkyl which isoptionally substituted by a radical selected from the group of hydroxy,halogen, cyano, C₁-C₆-alkoxy, trifluoromethyl, or trifluoromethoxy, R⁵represents hydrogen or C₁-C₆-alkyl; or R⁴ and R⁵ represent together withthe nitrogen atom to which they are bonded are a 5- to 6-memberedheterocycle which is optionally substituted by up to 2 substituentsindependently of one another selected from the group of C₁-C₆-alkyl,C₁-C₄-acyl, oxo, thioxo; R⁶ represents (i) hydrogen, (ii) C₁-C₆-alkyl,(iii) C₃-C₈-cycloalkyl, (iv) C₆-C₁₀-aryl, (v) 5- to 10-memberedheteroaryl, or (vi) C₆-C₁₀-arylcarbonyl, where (ii) is optionallysubstituted by phenyl, C₁-C₆-alkoxycarbonyl or C₁-C₆-alkoxy, and (iv),(v) and (vi) are optionally substituted by up to 3 radicals selectedindependently of one another from the group of C₁-C₆-alkyl,C₁-C₆-hydroxyalkyl, 3- to 8-membered heterocyclyl, C₆-C₁₀-aryl, 5- to10-membered heteroaryl, hydroxy, halogen, cyano, C₁-C₆-alkoxy,C₁-C₆-acyl, trifluoromethyl, trifluoromethoxy, nitro, amino,C₁-C₆-alkylamino, or C₁-C₆-acylamino; or R⁵ and R⁶ represent togetherwith the nitrogen atom to which they are bonded are a 3- to 10-memberedheterocycle which is optionally substituted by C₁-C₆-alkyl orC₁-C₆-hydroxyalkyl; A represents oxygen or sulfur; X represents oxygenor sulfur; ring B represents benzo which is optionally substituted byradicals from the series halogen, cyano, trifluoromethyl,trifluoromethoxy, nitro, amino, C₁-C₆-alkyl and C₁-C₆-alkoxy; or a saltthereof; and a pharmaceutically acceptable carrier.
 2. Thepharmaceutical composition of claim 1, wherein: R⁶ represents (i)hydrogen, (ii) C₁-C₆-alkyl, (iii) C₁-C₈-cycloalkyl, (iv) C₆-C₁₀-aryl, or(v) 5- to 10-membered heteroaryl, where (ii) is optionally substitutedby phenyl, or C₁-C₆-alkoxy, and (iv) and (v) are optionally substitutedby up to 3 radicals selected independently of one another from the groupof C₁-C₆-alkyl, C₁-C₆-hydroxyalkyl, 3- to 8-membered heterocyclyl,C₆-C₁₀-aryl, 5- to 10-membered heteroaryl, hydroxy, halogen, cyano,C₁-C₆-alkoxy, C₁-C₆-acyl, trifluoromethyl, trifluoromethoxy, nitro,amino, C₁-C₆-alkylamino, or C₁-C₆-acylamino; or R⁵ and R⁶ together withthe nitrogen atom to which they are bonded are a 3- to 8-memberedheterocycle which is optionally substituted by C₁-C₆-alkyl orC₁-C₆-hydroxyalkyl; and A represents oxygen.
 3. The pharmaceuticalcomposition of claim 1, wherein: R² represents hydrogen or C₁-C₄-alkyl;R³ represents hydrogen, halogen, amino, hydroxy or C₁-C₄-alkyl;represents hydrogen or C₁-C₄-alkyl which is optionally substituted by aradical selected from the group of hydroxy, halogen, cyano,C₁-C₃-alkoxy, trifluoromethyl or trifluoromethoxy; R⁵ representshydrogen or C₁-C₄-alkyl, or R⁴ and R⁵ represents together with thenitrogen atom to which they are bonded are a 5- to 6-memberedheterocycle which is optionally substituted by up to 2 substituentsindependently of one another selected from the group of C₁-C₆-alkyl,C₁-C₄-acyl, oxo, thioxo; R⁶ represents (i) hydrogen, (ii) C₁-C₄-alkyl,(iii) C₅-C₆-cycloalkyl, (iv) phenyl, (v) 5- to 6-membered heteroaryl, or(vi) C₆-C₁₀-arylcarbonyl, where (ii) is optionally substituted byphenyl, C₁-C₄-alkoxycarbonyl or C₁-C₃-alkoxy, and (iv), (v) and (vi) areoptionally substituted by up to 3 radicals selected independently of oneanother from the group of C₁-C₄-alkyl, C₁-C₄-hydroxyalkyl, 3- to8-membered heterocyclyl, C₆-C₁₀-aryl, 5- to 10-membered heteroaryl,hydroxy, fluorine, chlorine, cyano, C₁-C₃-alkoxy, C₁-C₃-acyl,trifluoromethyl, trifluoromethoxy, nitro, amino, C₁-C₃-alkylamino, orC₁-C₃-acylamino, or R⁵ and R⁶ together with the nitrogen atom to whichthey are bonded are a 3- to 10-membered heterocycle which is optionallysubstituted by C₁-C₃-alkyl or C₁-C₃-hydroxyalkyl; A represents oxygen; Xrepresents oxygen; and ring B represents benzo which is optionallysubstituted by radicals from the series chlorine, fluorine, cyano,trifluoromethyl, trifluoromethoxy, amino, C₁-C₄-alkyl and C₁-C₄-alkoxy.4. The pharmaceutical composition of claim 3, wherein: R⁴ representshydrogen or C₁-C₄-alkyl which is optionally substituted by a radicalselected from the group of hydroxy, C₁-C₃-alkoxy, trifluoromethyl,trifluoromethoxy; and R⁶ represents (i) hydrogen, (ii) C₁-C₄-alkyl,(iii) C₅-C₆-cycloalkyl, (iv) phenyl, or (v) 5- to 6-membered heteroaryl,where (ii) is optionally substituted by phenyl, and (iv) and (v) areoptionally substituted by up to 3 radicals selected independently of oneanother from the group of C₁-C₄-alkyl, C₁-C₄-hydroxyalkyl, hydroxy,chlorine, fluorine, cyano, C₁-C₃-alkoxy, C₁-C₆-acyl, trifluoromethyl,trifluoromethoxy, amino, C₁-C₃-alkylamino, or C₁-C₃-acylamino, or R⁵ andR⁶ together with the nitrogen atom to which they are bonded are a 5- to6-membered heterocycle which is optionally substituted by C₁-C₃-alkyl orC₁-C₃-hydroxyalkyl.
 5. The pharmaceutical composition of claim 1,wherein: R²-R⁴ each represents hydrogen; R⁵ represents hydrogen orC₁-C₄-alkyl, or R⁴ and R⁵ together with the nitrogen atom to which theyare bonded are a 5- to 6-membered heterocycle which is optionallysubstituted by up to 2 substituents independently of one anotherselected from the group of C₁-C₄-alkyl, C₁-C₄-acyl, oxo, thioxo; R⁶represents (i) hydrogen, (ii) C₁-C₄-alkyl, (iii) C₅-C₆-cycloalkyl, (iv)phenyl, (v) pyridyl, (vi) C₆-C₁₀-arylcarbonyl, where (ii) is optionallysubstituted by phenyl, C₁-C₄-alkoxycarbonyl or C₁-C₃-alkoxy, and (iv),(v) and (vi) are optionally substituted by up to 3 radicals selectedindependently of one another from the group of C₁-C₄-alkyl,C₁-C₄-hydroxyalkyl, 3- to 8-membered heterocyclyl, C₆-C₁₀-aryl, 5- to10-membered heteroaryl, hydroxy, fluorine, chlorine, cyano,C₁-C₃-alkoxy, C₁-C₃-acyl, trifluoromethyl, trifluoromethoxy, nitro,amino, C₁-C₃-alkylamino, or C₁-C₃-acylamino, or R⁵ and R⁶ together withthe nitrogen atom to which they are bonded are a 3- to 10-memberedheterocycle which is optionally substituted by C₁-C₃-alkyl orC₁-C₃-hydroxyalkyl; A represents oxygen; X represents oxygen; and ring Brepresents benzo.
 6. The pharmaceutical composition of claim 1, wherein:R² represents hydrogen; R³ represents hydrogen, chlorine, fluorine,amino or C₁-C₃-alkyl; R⁴ represents hydrogen, methyl or ethyl, wheremethyl and ethyl are optionally substituted by a radical selected fromthe group of hydroxy, methoxy, ethoxy, trifluoromethyl,trifluoromethoxy, or R⁴ and R⁵ together with the nitrogen atom to whichthey are bonded are a 5- to 6-membered heterocycle which is optionallysubstituted by up to 2 substituents independently of one anotherselected from the group of C₁-C₃-alkyl, C₁-C₄-acyl, oxo, thioxo; R⁵represents hydrogen or C₁-C₃-alkyl; R⁶ represents (i) hydrogen,C₁-C₄-alkyl, (iii) cyclohexyl, (iv) phenyl, benzyl, or (vi) phenethyl,where (iv) to (vi) are optionally substituted by up to 3 radicalsselected independently of one another from the group of hydroxy,chlorine, fluorine, cyano, methoxy, ethoxy, C₁-C₄-acyl, trifluoromethyl,trifluoromethoxy, amino, C₁-C₃-alkylamino; A represents oxygen; Xrepresents oxygen; and ring B represents benzo which is optionallysubstituted by radicals from the series chlorine, fluorine, cyano,trifluoromethyl, trifluoromethoxy, C₁-C₄-alkyl, methoxy and ethoxy. 7.The pharmaceutical composition of claim 1, wherein the compound isrepresented by formula:

wherein to R¹ to R⁶, A, and X have the meanings indicated in claim 1, ora salt thereof.
 8. The pharmaceutical composition of claim 1, whereinthe compound is represented by formula:

wherein R¹ to R⁶, A, and X have the meanings indicated in claim 1, or asalt thereof.
 9. The pharmaceutical composition of claim 1, wherein thecompound is represented by formula:

wherein R¹ to R⁶ have the meanings indicated in claim 1, or a saltthereof.
 10. The pharmaceutical composition of claim 1, wherein thecompound is represented by formula:

wherein R¹ to R⁶ have the meanings indicated in claim 1, or a saltthereof.
 11. The pharmaceutical composition of claim 1, wherein: R²-R⁵each represents hydrogen; R⁶ represents (i) hydrogen, (ii) C₁-C₆-alkyl,(iii) C₃-C₈-cycloalkyl, (iv) C₆-C₁₀-aryl, (v) 5- to 10-memberedheteroaryl, (vi) C₆-C₁₀-arylcarbonyl, where (ii) is optionallysubstituted by phenyl, C₁-C₆-alkoxycarbonyl or C₁-C₆-alkoxy, and (iv),(v) and (vi) are optionally substituted by up to 3 radicals selectedindependently of one another from the group of C₁-C₆-alkyl,C₁-C₆-hydroxyalkyl, 3- to 8-membered heterocyclyl, C₆-C₁₀-aryl, 5- to10-membered heteroaryl, hydroxy, halogen, cyano, C₁-C₆-alkoxy,C₁-C₆-acyl, trifluoromethyl, trifluoromethoxy, nitro, amino,C₁-C₆-alkylamino, or C₁-C₆-acylamino; A represents sulfur; X representsoxygen; and ring B represents benzo.
 12. The pharmaceutical compositionof claim 11, wherein: R⁶ (i) hydrogen, (ii) C₁-C₆-alkyl, (iii)C₃-C₈-cycloalkyl, (iv) C₆-C₁₀-aryl, (v) 5- to 10-membered heteroaryl,where (ii) is optionally substituted by phenyl, or C₁-C₆-alkoxy, and(iv) and (v) are optionally substituted by up to 3 radicals selectedindependently of one another from the group of C₁-C₆-alkyl,C₁-C₆-hydroxyalkyl, 3- to 8-membered heterocyclyl, C₆-C₁₀-aryl, 5- to10-membered heteroaryl, hydroxy, halogen, cyano, C₁-C₆-alkoxy,C₁-C₆-acyl, trifluoromethyl, trifluoromethoxy, nitro, amino,C₁-C₆-alkylamino, or C₁-C₆-acylamino.
 13. The pharmaceutical compositionof claim 11, wherein: R⁶ represents (i) hydrogen, (ii) C₁-C₄-alkyl,(iii) C₅-C₆-cycloalkyl, (iv) phenyl, (v) 5- to 6-membered heteroaryl,(vi) C₆-C₁₀-arylcarbonyl, where (ii) is optionally substituted byphenyl, C₁-C₄-alkoxycarbonyl or C₁-C₃-alkoxy, and (iv), (v) and (vi) areoptionally substituted by up to 3 radicals selected independently of oneanother from the group of C₁-C₄-alkyl, C₁-C₄-hydroxyalkyl, 3- to8-membered heterocyclyl, C₆-C₁₀-aryl, 5- to 10-membered heteroaryl,hydroxy, fluorine, chlorine, cyano, C₁-C₃-alkoxy, C₁-C₃-acyl,trifluoromethyl, trifluoromethoxy, nitro, amino, C₁-C₃-alkylamino, orC₁-C₃-acylamino.
 14. The pharmaceutical composition of claim 11,wherein: R⁶ represents (i) hydrogen, (ii) C₁-C₄-alkyl, (iii)C₅-C₆-cycloalkyl, (iv) phenyl, (v) 5- to 6-membered heteroaryl, where(ii) is optionally substituted by phenyl, and (iv) and (v) areoptionally substituted by up to 3 radicals selected independently of oneanother from the group of C₁-C₄-alkyl, C₁-C₄-hydroalkyl, hydroxy,chlorine, fluorine, cyano, C₁-C₃-alkoxy, C₁-C₆-acyl, trifluoromethyl,trifluoromethoxy, amino, C₁-C₃-alkylamino, or C₁-C₃-acylamino.
 15. Thepharmaceutical composition of claim 11, wherein: R⁶ represents (i)hydrogen, (ii) C₁-C₄-alkyl, (iii) C₅-C₆-cycloalkyl, (iv) phenyl, (v)pyridyl, (vi) C₆-C₁₀-arylcarbonyl, where (ii) is optionally substitutedby phenyl, C₁-C₄-alkoxycarbonyl or C₁-C₃-alkoxy, and (iv), (v) and (vi)are optionally substituted by up to 3 radicals selected independently ofone another from the group of C₁-C₄-alkyl, C₁-C₄-hydroxyalkyl, 3- to8-membered heterocyclyl, C₆-C₁₀-aryl, 5- to 10-membered heteroaryl,hydroxy, fluorine, chlorine, cyano, C₁-C₃-alkoxy, C₁-C₃-acyl,trifluoromethyl, trifluoromethoxy, nitro, amino, C₁-C₃-alkylamino, orC₁-C₃-acylamino.
 16. The pharmaceutical composition of claim 11,wherein: R⁶ represents (i) hydrogen, (ii) C₁-C₄-alkyl, (iii)cyclopentyl, cyclohexyl, (iv) phenyl, (v) benzyl, (vi) phenethyl, where(iv) to (vi) are optionally substituted by up to 3 radicals selectedindependently of one another from the group of hydroxy, chlorine,fluorine, cyano, methoxy, ethoxy, C₁-C₄-acyl, trifluoromethyl,trifluoromethoxy, amino, C₁-C₃-alkylamino.
 17. The pharmaceuticalcomposition of claim 11, wherein the compound is represented by formula:

wherein R¹ to R⁶, A, and X have the meanings indicated in claim 11, or asalt thereof.
 18. The pharmaceutical composition of claim 11, whereinthe compound is represented by formula:

wherein R¹ to R⁶, A, and X have the meanings indicated in claim 11, or asalt thereof.
 19. The pharmaceutical composition of claim 11, whereinthe compound is represented by formula:

wherein R¹ to R⁶ have the meanings indicated in claim 11, or a saltthereof.
 20. The pharmaceutical composition of claim 11, wherein thecompound is represented by formula:

wherein R¹ to R⁶ have the meanings indicated in claim 11, or a saltthereof.